This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).

The domino three-component coupling reaction of arynes with DMF and active methylenes or methines was studied as a highly efficient method for preparing heterocycles. Coumarin derivative 5 was formed when diethyl malonate (2) or α-bromomalonate (3) were used as a C2-unit. In contrast, dihydrobenzofurans 7a and 7b were obtained by using α-chloroenolates generated from α-chloromalonates 4a and 4b and Et2Zn. The benzofuran 15a could be obtained by using ethyl iodoacetate (14) as a C1-unit. The one-pot conversion of dihydrobenzofurans 7a, 7b and 8a into benzofurans 15a and 15b was also studied. The direct synthesis of benzofuran 15b was achieved by using the active methine 18 having ketone and ester groups.

Synthetic strategies involving domino or cascade process offer the advantage of multiple carbon-carbon and/or carbon-heteroatom bond formations in a single operation [1]. In recent years, the domino reactions using arynes continue to attract much interest [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21], since arynes are highly reactive species for constructing the multi-substituted arenes with structural diversity and complexity [22,23].

The recent aryne-based chemistry has achieved some remarkable success in the transition metal-catalyzed reactions [2,3,4,5,6,7,8,9,10], the transition metal-free reactions and other transformations [11,12,13,14,15,16,17,18,19,20,21]. These advances have shown that the insertion of arynes into various element-element σ-bonds can be achieved even under the transition metal-free conditions. We have been interested in developing the corresponding π-bond insertion [24,25,26,27,28,29,30,31]. Recently, we reported the efficient insertion into the C=O bond of formamides [32,33], which was successfully applied into the domino process trapping the transient intermediates with nucleophiles [34,35,36]. In this paper, we describe in detail our approach to prepare coumarin, dihydrobenzofuran and benzofuran derivatives via the three-component coupling process starting from arynes generated from ortho-(trimethylsilyl)aryl triflates.

2. Results and Discussion2.1. New Approach for the Domino Three-Component Coupling Process

The goal of our study on aryne chemistry is to develop the highly efficient domino reactions for preparing heterocycles. Therefore, we have designed a new approach involving two steps which are induced by the high reactivity related to the strain energy of aryne A and the four-membered intermeditate B (Scheme 1) [37].

The insertion of a highly strained aryne A, generated in situ from ortho-(trimethylsilyl)aryl triflate 1 and the fluoride ion [38], into the C=O of N,N-dimethylformamide (DMF) gives the moderately strained [2+2] adduct benzoxetene B, which would undergo isomerized into ortho-quinone methide C (Step 1). The sequential transformation can be achieved by the initial addition of nucleophiles to the transient intermediate C and the subsequent trapping process with electrophiles (Step 2). When nucleophile and electrophile belong to the same molecule as shown in Scheme 1, the use of C2-units (X–Y) leads to the products D and the use of C1-units (X) leads to the products E.

molecules-19-00863-scheme1_Scheme 1Scheme 1

Three-component coupling reaction.

For the synthesis of products D such as coumarin derivatives, we used enol F and enolate G having both nucleophilic and electrophilic sites, which were derived from malonate 2 and α-bromomalonate 3, respectively (Scheme 2). For the synthesis of products E such as dihydrobenzofurans and benzofurans, α-chloroenolate H having a nucleophilic and electrophilic carbon atom, derived from α-chloromalonate 4, was employed for trapping the unstable intermediate C.

molecules-19-00863-scheme2_Scheme 2Scheme 2

Substrates for trapping the intermediate C.

2.2. The Synthesis of Coumarin Derivative

In organic synthesis, DMF can react as either an electrophilic or nucleophilic agent [39,40]. At first, we examined the reaction of 3-methoxy-2-(trimethylsilyl)phenyl triflate (1) as an aryne precursor with DMF and diethyl malonate (2) as a C2-unit (Table 1). It is well known that the active methylenes such as diethyl malonate (2) have an excellent reactivity toward arynes giving the σ-bond insertion products [41,42,43,44,45]. To suppress the competitive insertion of aryne into the C–C σ-bond of 2, DMF was employed as a solvent. We were gratified to observe the sufficient reactivity of active methylene 2 toward intermediate B in the absence of base. The effect of fluoride ion sources was studied. In the presence of CsF, treatment of triflate 1 with 2 in DMF at room temperature predominantly gave the desired coumarin 5 in 65% yield, accompanied by a trace amount of salicylaldehyde derivative 6 (entry 1). The replacement of CsF with anhydrous TBAF led to an increase in the chemical yield to give 5 in 86% yield (entry 2). In contrast, no reaction was observed when KF was employed (entry 3).

This domino transformation involves the trapping reaction of the unstable intermediate C with enol F giving the intermediate I (Scheme 3). The coumarin 5 was formed via the elimination of a dimethylamino group from the intermediate I.

molecules-19-00863-scheme3_Scheme 3Scheme 3

Reaction pathway.

Further investigations using α-bromomalonate 3 and organometallic reagents such as Et2Zn or Me3Al were performed (Table 2). In the presence of Et2Zn, we initially allowed triflate 1 to react with 3 in DMF at room temperature for 12 h (entry 1). The desired coumarin 5 was obtained in 11% yield, accompanied by the recovered triflate 1 in 64%. Although the replacement of CsF with anhydrous TBAF led to an increase in the chemical yield, the new formation of dihydrobenzofuran 7a was observed (entry 2). The reaction did not take place when KF was employed (entry 3). Therefore, Me3Al was next employed (entries 4 and 5). In the presence of CsF, treatment of 1 with 3 in DMF predominantly gave the desired product 5 in 34% yield (entry 4). Improvement in the chemical yield of 5 was observed when anhydrous TBAF was used (entry 5). The chemical yield increased into 85%. In this transformation, a suitable combination of α-bromomalonate 3 and Me3Al led to the efficient generation of the debrominated metal enolate G, which reacted with intermediate C to give coumarin 5.

We next investigated the domino reaction for the synthesis of dihydrobenzofurans (Table 3). The key issue of this transformation is the efficient generation of α-halogenated enolate as a C1-unit. However, as mentioned above, the debromination took place when α-bromomalonate 3 and organometallic reagents were employed. In remarked contrast to α-bromomalonate 3, we found that the use of α-chloromalonates 4a,b and Et2Zn led to the generation of desired α-halogenated enolates H (Scheme 4). Thus, a combination of α-chloromalonates 4a,b and Et2Zn was checked under the different reaction conditions for the synthesis of dihydrobenzofurans.

In the presence of anhydrous TBAF, treatment of triflate 1 with 4a in DMF at room temperature gave the desired product 7a in 21% yield, accompanied by 64% yield of undesired dihydrobenzofuran 8a (entry 1). The undesired dihydrobenzofuran 8a having a hydroxy group would be formed as a result of hydrolysis of intermediates B or C with contamining water. The isolated yield of 7a increased to 66% yield by changing the reaction temperature (entry 2). The formation of undesired product 8a was not observed when CsF was employed (entries 3 and 4). In particular, improvement in the chemical yield of 7a was observed, when 1.2 equivalents of triflate 1 was reacted with 1.0 equivalent of 4a in DMF (entry 4). Similar trend was observed in the reaction using α-chloromalonate 4b (entries 6 and 7). In the presence of CsF and Et2Zn, treatment of triflate 1 (1.2 equiv) with 4b (1.0 equiv) in DMF at −40 °C to room temperature for 12 h gave the desired dihydrobenzofuran 7b in 89% yield (entry 7).

In this transformation, α-chloroenolates H are effectively generated from α-chloromalonates 4a,b and Et2Zn (Scheme 4). These α-halogenated enolates H work as not only a nucleophile to attack to the intermediate C but also an electrophile to trap intramolecularly the intermediate anion J to give the desired dihydrobenzofurans 7a,b.

The reactivity of α-chloromalonate 4a toward arynes was also investigated (Scheme 5). In the presence of CsF, the direct reaction of triflate 1 with 4a was carried out in CH3CN without DMF. As expected, the σ-bond insertion product 9 was obtained in 52% yield.

molecules-19-00863-scheme5_Scheme 5Scheme 5

Reaction of 1 with 4a.

As mentioned above, the competitive insertion of aryne into the C–C σ-bond of 4a was not observed in the domino three-component coupling reaction of bulky triflate 1. Decreasing the steric hindrance around the triple bond of aryne induced the direct insertion of aryne into α-chloromalonate 4a. When sterically less hindered triflate 10 was employ as an aryne precursor, the σ-bond insertion product 12 was obtained in 51% yield (Scheme 6). To suppress the competitive insertion of aryne into 4a, the concentration was evaluted. Under the high diluted concentration (0.02 M solution of 10 in DMF), the σ-bond insertion was mostly suppressed to afford the desired dihydrobenzofuran 11 in 65% yield, accompanied by 14% yield of dihydrobenzofuran 13 having a hydroxy group.

molecules-19-00863-scheme6_Scheme 6Scheme 6

Reaction of 10 with DMF and 4a.

2.4. The Synthesis of Benzofurans

With these results in mind, the synthesis of benzofurans was next studied (Table 4). At first, ethyl iodoacetate 14 was employed as a C1-unit. The reaction of triflate 1 with 14 was run in DMF in the presence of 3.0 equivalents of TBAF (entry 1). However, the simple O-alkylated product 16 was formed in 28% yield, accompanied by salicylaldehyde derivative 6 in 45% yield. The similar trend was observed when CsF was used (entry 2). The reaction temperature had an impact on the chemical transformation (entry 3). The desired benzofuran 15a was obtained in 40% yield, when reaction was run at 100 °C. The use of Et2Zn or Me3Al as additive was not effective for this reaction (entries 4 and 5).

molecules-19-00863-t004_Table 4Table 4

Reaction of aryne precursor 1 with DMF and 14a.

Entry

Reagent (equiv)

Ethyl iodoacetate

T (°C)

Time (h)

Product (% yield) b

1

TBAF (3.0)

1.5 equiv

rt

12

16 (28), 6 (45)

2

CsF (3.0)

1.5 equiv

rt

12

16 (44), 6 (34)

3

CsF (5.0)

2.0 equiv

100

3

15a (40), 16 (trace), 6 (11)

4 c

CsF (5.0)

2.0 equiv

rt

24

Complex mixture d

5 e

CsF (5.0)

2.0 equiv

rt

24

NR f

a Reactions were carried out with 1 (1.0 equiv), 14 (1.5 or 2.0 equiv), and reagent (3.0 or 5.0 equiv) in DMF (0.1 M solution of 1). b Isolated yield. c Reaction was carried out in the presence of Et2Zn (2.0 equiv). d Triflate 1 was recovered in 36% yield. e Reaction was carried out in the presence of Me3Al (2.0 equiv). f No reaction; Triflate 1 was recovered in 79% yield.

To understand the reaction pathway, the formation of benzofuran 15a from the simple O-alkylated product 16 was studied (Scheme 7). As expected, benzofuran 15a was obtained in 32% yield, after being stirred at room temperature for 12 h followed by heated at 100 °C for 12 h. Thus, benzofuran 15a could be obtained from O-alkylated product 16.

molecules-19-00863-scheme7_Scheme 7Scheme 7

Conversion of 16 into 15a.

For the formation of benzofuran 15a, two possible reaction pathways are shown in Scheme 8. As a direct pathway, benzofuran 15a is assumed to be obtained from ortho-quinone methide C and 14 via intermediate K (path a). Another pathway is the formation of benzofuran 15a from the simple O-alkylated product 16 via intermediates L and M (path b).

molecules-19-00863-scheme8_Scheme 8Scheme 8

Two reaction pathways.

As an alternative approach for synthesis of benzofurans, we tried to establish the conversion of dihydrobenzofurans 7a and 7b into benzofurans 15a and 15b (Scheme 9). When dihydrobenzofuran 7a was treated with 2.5 equivalents of EtMgBr followed by SiO2, the disered benzofuran 15a was obtained in 77% yield without the isolation of adduct 17a. Similarly, benzofuran 15b was formed form dihydrobenzofuran 7b. These transformations would proceed via the retro-aldol type reaction of adducts 17a and 17b followed by the elimination of a dimethylamino group.

molecules-19-00863-scheme9_Scheme 9Scheme 9

Conversion of 7a,b into 15a,b.

Next, we directed our attention into the direct one-pot synthesis of benzofuran 15b (Scheme 10). For this purpose, the active methine 18 having ketone and ester groups was used, since ketone moiety would selectively react with Et2Zn, leading to the retro-aldol type process. In the presence of CsF, triflate 1 and methine 18 in DMF were treated with Et2Zn (1.0 equiv + 0.5 equiv) at −60 °C to room temperature for 12 h. As expected, the desired benzofuran 15b having an ester group was directly generated via the addition of an ethyl anion to a ketone group of dihydrobenzofuran O, the retro-aldol type reaction of intermediate P and the elimination of a dimethylamino group of anion Q.

molecules-19-00863-scheme10_Scheme 10Scheme 10

Direct one-pot synthesis of benzofuran 15b.

Finally, we investigated the transformation of dihydrobenzofuran 8a having a hydroxy group into benzofuran 15a (Scheme 11) [46]. As a starting substrate, the preparation of dihydrobenzofuran 8a was initially studied. When the domino reaction of triflate 1 with α-bromomalonate 3 and DMF was carried out in the presence of water (1.0 equiv), the desired dihydrobenzofuran 8a was obtained in 77% yield instead of dihydrobenzofuran 7a having a dimethylamino group. For the synthesis of benzofuran 15a, we next allowed dihydrobenzofuran 8a to react with several bases (Table 5). Treatment of dihydrobenzofuran 8a with 1.0 equivalent of NaH in DMF at room temperature gave the desired benzofuran 15a in 83% yield (entry 1). Probably, this transformation proceeds via the decarboxylation of cyclic intermediate R. In contrast, benzofuran 15a was not obtained when LiHMDS was employed in THF at −40 °C (entry 2). Interestingly, the replacement of LiHMDS with NaHMDS led to the formation of 15a (entry 3). The isolated yield of 15a dramatically increased to 96% yield by replacing NaHMDS with KHMDS (entry 4).

Melting points were taken on a Yanaco MP-J3 and are uncorrected. Infrared spectra were measured on a JASCO FT/IR-4100. 1H-NMR spectra were measured on a JEOL ECX-400 PSK (400 MHz) or Varian NMRS 600 (600 MHz). 13C-NMR spectra were measured on a JEOL ECX-400 PSK (101 MHz) or Varian NMRS 600 (151 MHz) with CDCl3 as an internal standard (77.0 ppm). High resolution mass spectra were obtained by use of a Hitachi M-4100 GC/MS spectrometer or Thermo Fisher Scientific Exactive LC/MS spectrometer. For silica gel column chromatography, SiliCycle Inc. SiliaFlash F60 was used. The anhydrous TBAF was prepared from TBAF·3H2O by heating the hydrate at 40 °C for 6 h, at 60 °C for 12 h, at 80 °C for 6 h, and then at 120 °C for 12 h under reduced pressure [47]. The prepared anhydrous TBAF was used as a solution by addition of appropriate solvent such as DMF.

3.2. Procedure for the Synthesis of Coumarin Derivative 5 using Malonate 2

3.3. Procedure for the Synthesis of Coumarin Derivative 5 using α-Bromomalonate 3

To a solution of diethyl α-bromomalonate (3, 68 µL, 0.40 mmol) in DMF (1.5 mL) was added Me3Al (1.08 M in hexane, 370 µL, 0.40 mmol) under argon atmosphere at room temperature. After being stirred at the same temperature for 5 min, 3-methoxy-2-(trimethylsilyl)phenyl triflate (1, 53 µL, 0.20 mmol) and TBAF (264 mg, 1.00 mmol) in DMF (0.5 mL) were added to the reaction mixture. After being stirred at the same temperature for 12 h, the reaction mixture was diluted with saturated NaHCO3 and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica gel column chromatography (AcOEt/hexane = 1:20–1:1 with 2% CH2Cl2) afforded coumarin derivative 5 (42 mg, 85%).

3.4. Typical Procedure for the Synthesis of Dihydrobenzofurans

To a suspension of CsF (183 mg, 1.20 mmol) in DMF (2.0 mL) was added Et2Zn (1.0 M in toluene, 200 µL, 0.20 mmol) under argon atmosphere at −40 °C. After being stirred at the same temperature for 5 min, diethyl α-chloromalonate 4a (32 µL, 0.20 mmol) and 3-methoxy-2-(trimethylsilyl)phenyl triflate (1, 63 µL, 0.24 mmol) were added to the reaction mixture. After being stirred at −40 °C to room temperature for 12 h, silica gel (0.5 g) was added to the reaction mixture, and then it was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (EtOAc/hexane = 1:20–1:4) afforded dihydrobenzofuran 7a (58.0 mg, 86%). Under similar reaction conditions, dihydrobenzofurans 7b and 11 were synthesized. Products 8a, 12 and 13 were also formed.

To a suspension of CsF (304 mg, 2.0 mmol) in DMF (4.0 mL) were added 3-methoxy-2-(trimethylsilyl)phenyl triflate (1, 105 µL, 0.40 mmol) and ethyl iodoacetate 14 (95 µL, 0.80 mmol) under argon atmosphere at 100 °C. After being stirred at the same temperature for 12 h, the reaction mixture was diluted with saturated NaHCO3 and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated at reduced pressure. Purification of the residue by flash silica gel column chromatography (EtOAc/hexane = 1:20–1:4) afforded the product 15a (35 mg, 40%). Product 16 was also formed.

3.7. Typical Procedure for Conversion of Dihydrobenzofurans into Benzofurans

To a solution of 7a (40.0 mg, 0.12 mmol) in THF (2.4 mL) was added EtMgBr (1.0 M in THF, 300 µL, 0.30 mmol) under argon atmosphere at −40 °C. After being stirred at −40 °C to room temperature for 3 h, the reaction mixture was diluted with saturated NH4Cl and then extracted with AcOEt. The organic phase was dried over Na2SO4 and concentrated at reduced pressure to give quantitatively the crude adduct 17a, which was used for next reaction without further purification. To a solution of 17a (35.2 mg, 0.10 mmol) in AcOEt (1.0 mL) was added silica gel (0.50 g) under the atmosphere at room temperature. After being stirred for 12 h, the reaction mixture was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (EtOAc/hexane = 1:10–1:3) afforded the product 15a (16.9 mg, 77%).

To a suspension of CsF (183 mg, 1.20 mmol) in DMF (2.0 mL) was added Et2Zn (1.0 M in toluene, 200 µL, 0.20 mmol) under argon atmosphere at −60 °C. After being stirred at the same temperature for 5 min, methyl 2-chloroacetoacetate (18, 24 µL, 0.20 mmol) and 3-methoxy-2-(trimethylsilyl)phenyl triflate (1, 63 µL, 0.24 mmol) were added to the reaction mixture. After being stirred at −60 °C to room temperature for 12 h, Et2Zn (1.0 M in toluene, 100 µL, 0.10 mmol) was added to the reaction mixture. After being stirred for 3 h, silica gel (0.5 g) was added to the reaction mixture, and then it was concentrated under reduced pressure. Purification of the residue by flash silica gel column chromatography (EtOAc/hexane = 1:20–1:4) afforded the product 15b (19.9 mg, 48%).

3.9. Procedure for Transformation of Dihydrobenzofuran 8a into Benzofuran 15a

To a solution of dihydrobenzofuran 8a (50 mg, 0.16 mmol) in THF (3.2 mL) was added KHMDS (0.50 M in toluene, 320 µL, 0.16 mmol) under argon atmosphere at −40 °C. After being stirred at the same temperature for 12 h, the reaction mixture was diluted with saturated NaHCO3 and then extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated at reduced pressure. Purification of the residue by PTLC (EtOAc/hexane = 1:4 with 2% CH2Cl2) afforded benzofuran 15a (33 mg, 96%).

4. Conclusions

We have demonstrated that the domino three-component coupling reaction of arynes with DMF and active methylenes or methines gave various heterocycles such as coumarin derivatives, dihydrobenzofurans and benzofurans.

Acknowledgments

This work was partially supported by JSPS KAKENHI Grant-in-Aid for Young Scientists (B) Grant Number 24790032.

Author Contributions

E. Yoshioka performed experiments and analyzed the data. S. Kohtani carried out part of the data analysis and experiments. H. Miyabe contributed to design of the study and manuscript writing.

37.MeierH.Benzoxetes and benzothietes—Heterocyclic analogues of benzocyclobuteneMolecules2012171548157010.3390/molecules1702154838.HimeshimaY.SonodaT.KobayashiH.Fluoride-induced 1,2-elimination of o-trimethylsilylphenyl triflate to benzyne under mild conditionsChem. Lett.1983121211121410.1246/cl.1983.121139.MuzartJ.N,N-Dimethylformamide: Much more than a solventTetrahedron2009658313832310.1016/j.tet.2009.06.09140.DingS.JiaoN.N,N-Dimethylformamide: A multipurpose building blockAngew. Chem. Int. Ed.2012519226923741.YoshidaH.WatanabeM.MorishitaT.OhshitaJ.KunaiA.Straightforward construction of diarylmethane skeletons via aryne insertion into carbon-carbon σ-bondsChem. Commun.20071505150742.YoshidaH.KishidaT.WatanabeM.OhshitaJ.Fluorenes as new molecular scaffolds for carbon-carbon σ-bond cleavage reaction: Acylfluorenylation of arynesChem. Commun.20085963596543.LiuY.-L.LiangY.PiS.-F.LiJ.-H.Selective synthesis of o-acylbenzylphosphonates by insertion reactions of arynes into β-ketophosphonatesJ. Org. Chem.2009745691569410.1021/jo900847u44.TadrossP.M.VirgilS.C.StoltzB.M.Aryne acyl-alkylation in the general and convergent synthesis of benzannulated macrolactone natural products: An enantioselective synthesis of (−)-curvularinOrg. Lett.2010121612161410.1021/ol100335y45.TadrossP.M.GilmoreC.D.BuggaP.VirgilS.C.StoltzB.M.Regioselective reactions of highly substituted arynesOrg. Lett.2010121224122710.1021/ol100079646.WitiakD.T.NewmanH.A.I.PoochikianG.K.FogtS.W.BaldwinJ.B.SoberC.L.FellerD.R.Diethyl (4bα,4cα,9aα,9bα)-3,6-dichlorocyclobuta [1,2-b:3,4-b']bisbenzofuran-9a,9b(4bH,4cH)-dicarboxylate: The cis,syn photodimer of ethyl 5-chlorobenzofuran-2-carboxylatea, an analogue related to the antilipidemic drug clofibrateJ. Med. Chem.19782183383710.1021/jm00206a02647.